17-81528550-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012418.4(FSCN2):c.19C>T(p.His7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,601,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: FSCN2 NM_012418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

Genes affected

FSCN2 (HGNC:3960): (fascin actin-bundling protein 2, retinal) This gene encodes a member of the fascin protein family. Fascins crosslink actin into filamentous bundles within dynamic cell extensions. This family member is proposed to play a role in photoreceptor disk morphogenesis. A mutation in this gene results in one form of autosomal dominant retinitis pigmentosa and macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1726377).
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FSCN2	NM_012418.4	c.19C>T	p.His7Tyr	missense_variant	1/5	ENST00000417245.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FSCN2	ENST00000417245.7	c.19C>T	p.His7Tyr	missense_variant	1/5	1	NM_012418.4	P1
FSCN2	ENST00000334850.7	c.19C>T	p.His7Tyr	missense_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000827 AC: 19 AN: 229664 Hom.: 0 AF XY: 0.0000957 AC XY: 12 AN XY: 125400

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000785

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000835 AC: 121 AN: 1449536 Hom.: 0 Cov.: 32 AF XY: 0.0000861 AC XY: 62 AN XY: 720050

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.0000772

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000913

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152360 Hom.: 0 Cov.: 34 AF XY: 0.0000939 AC XY: 7 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000332 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 7 of the FSCN2 protein (p.His7Tyr). This variant is present in population databases (rs782450097, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 16280978). ClinVar contains an entry for this variant (Variation ID: 857253). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	0.0072
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.082
Sift	Benign	0.26	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.94	P;.
Vest4		0.37
MutPred		0.29		Gain of catalytic residue at H7 (P = 0.0498);Gain of catalytic residue at H7 (P = 0.0498);
MVP		0.50
MPC		0.13
ClinPred		0.093	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782450097; hg19: chr17-79495576;